Safety of bariatric surgery in patients with previous acute coronary events or heart failure: nationwide cohort study

Abstract Background Metabolic (bariatric) surgery for patients with severe obesity and pre-existing heart disease has been reported to reduce the risk for cardiovascular events and mortality; however, concerns of short- and mid-term complications may limit the utility of metabolic surgery for these patients. Method This was an observational, nationwide, matched study, including all adult patients operated with a primary gastric bypass or sleeve gastrectomy procedure in Sweden from January 2011 until October 2020. Patients with or without previous acute coronary syndrome or heart failure were matched 1:5 using propensity scores. The primary outcome was serious postoperative complications, and secondary outcomes were the occurrence of any short-term complications, mid-term complications, weight loss, and health-related quality of life estimates after surgery Results Of patients who underwent metabolic surgery, 1165 patients with previous acute coronary syndrome or heart failure and 5825 without diagnosed heart disease were included in matched analyses. No difference was seen between the groups at risk for serious postoperative complications within 30 days of surgery (OR 1.33, 95 per cent c.i. 0.95 to 1.86, P = 0.094), whereas heart disease was associated with an increased risk for cardiovascular complications (incidence 1.1 per cent versus 0.2 per cent, P < 0.001). No differences in overall mid-term complications, weight loss, or improvement of health-related quality of life were seen. Pre-existing heart disease was associated with an increased risk for bowel obstruction and strictures (OR 1.89, 95 per cent c.i. 1.20 to 2.99, P = 0.006). Conclusion Patients with severe obesity and heart disease undergoing metabolic surgery have an increased risk of postoperative cardiovascular complications compared with patients with severe obesity without heart disease. A careful preoperative cardiovascular work-up is needed but patients with severe obesity and heart disease should not be excluded from undergoing metabolic surgery.


Introduction
There is a clear association between severe obesity and type 2 diabetes (T2D) and the associated insulin resistance, dyslipidaemia, and hypertension. These co-morbidities also increase the risk for cardiovascular disease. The evidence for treating T2D in patients with severe obesity with metabolic (bariatric) surgery is strong following several randomized clinical trials (RCTs) 1,2 . Over the past decade there is also increasing evidence from observational studies that metabolic surgery significantly reduces the risk for cardiovascular disease such as myocardial infarction, stroke, and cardiovascular death 3 . Metabolic surgery was associated with a reduced rate of all-cause and cardiovascular death in a recent meta-analysis of 18 observational studies 4 . There is currently one RCT that has shown a superior effect of metabolic surgery on hypertension compared with conventional treatment 5 .
While metabolic surgery has a role in primary prevention, it has been proposed that metabolic surgery has also a role in secondary prevention of cardiovascular disease. Metabolic surgery is associated with a lower risk of major adverse cardiovascular events (MACEs) in patients with severe obesity and hypertension 6 , a previous myocardial infarction 7 , or ischaemic heart disease or heart failure 8 , and the risk of MACE is reduced by half in patients that go into remission of their hypertension compared with those who do not 9 . One of the reasons why cardiologists and surgeons might be reluctant to suggest metabolic surgery to a patient with pre-existing cardiovascular disease is a paucity in data regarding short-and mid-term postoperative complications 10,11 .
The aim of the present study was to assess both short-and mid-term complications in patients with severe obesity and pre-existing heart disease who undergo metabolic surgery.

Methods
This observational, matched cohort study was based on data from the Scandinavian Obesity Surgery Registry (SOReg), a national research and quality register that started in 2007 covering virtually all bariatric surgical procedures in Sweden (52 reporting centres during the study interval). The registry is continuously validated and registrations have so far been shown to have very high validity 12

Inclusion and exclusion
While there were no mandatory national eligibility criteria for metabolic surgery in Sweden during the study interval, most regions in Sweden considered a slightly more liberal approach compared with the National Institutes of Health criteria from 1991 15 , with BMI of 35 kg/m 2 or more with or without co-morbidity as an eligibility criterion.
All patients aged at least 18 years who had a primary sleeve gastrectomy or gastric bypass from 1 January 2011 until 8 October 2020 were included in the study. Heart disease was specified as previous history of an acute coronary syndrome (ACS), heart failure, or cardiomyopathy, defined as hospital admission for unstable angina pectoris (ICD-10, I20.0), myocardial infarction (ICD-10, I21-22), heart failure (ICD-10, I50) or cardiomyopathy (ICD-10, I42) before surgery, or a diagnosis of heart failure or cardiomyopathy in the NPR for outpatient care if dispensed loop diuretics (ATC-code, C03C), beta-blockers (ATC-code, C07A), ACE-inhibitor or angiotensin-II inhibitor (ATC-code, C09A, C09B, or C09C) within 12 months before surgery.

Matching procedure
Patients with a preoperative episode of ACS or heart failure were matched 1:5 with controls who underwent metabolic surgery without a preoperative diagnosis of ACS or heart failure. The matching was conducted as a two-stage procedure with a first exact match on surgical method (bypass or sleeve), followed by a propensity score match (nearest function without limit for calliper), including age, sex, preoperative BMI, surgical centre, year of surgery, hypertension, diabetes, sleep apnoea, dyslipidaemia, depression, and level of education.

Definitions
Co-morbidity was defined as an obesity-related condition (specified as diabetes, dyslipidaemia, hypertension, or sleep apnoea), or depression requiring active pharmacological or continuous positive-airway pressure treatment.
History of smoking was based on self-reporting at baseline. Level of education was divided into three categories based on the highest completed education at the time of surgery: primary education (9 years of schooling or fewer), secondary education (completed 10-12 years of schooling), or higher education (completed college or university degree).

Procedures
The surgical technique for the laparoscopic gastric bypass procedure was highly standardized in Sweden during the study interval and was an antecolic, antegastric Roux-en-Y gastric bypass (RYGB) with a small gastric pouch (less than 25 ml), an alimentary limb of 100 cm, and a biliopancreatic limb of 50 cm. The sleeve gastrectomy (SG) was less standardized, but most operations were routinely performed using a 32-36 Fr Bougie, starting the resection 5 cm or less from the pylorus, ending the resection 1 cm lateral to the angle of His.

Endpoints
The main outcome was serious postoperative complication within 30 days of surgery. A serious postoperative complication was defined as a complication graded 3b or above on the Clavien-Dindo scale (a complication requiring an intervention under general anaesthesia, single or multiple organ failure, or death) 16 . Data on mortality were based on combined data from the total population registry (reporting complete coverage of mortality), and the SOReg, NPR, and Cause of Death Registry for cause of death. Secondary outcomes were the occurrence of any short-term postoperative complication within 30 days of surgery (defined as a specific complication requiring prolonged duration of hospital stay, readmission, or intervention, thus deviating from a normal postoperative course), mid-term complications (30 day -2 year follow-up, defined as treatment, or readmission for anaemia, malnutrition, marginal ulcer, bowel obstruction/ stricture, or leak/gastric or intestinal perforation), postoperative weight loss measured as percentage total weight loss (TWL), excess BMI loss (EBMIL), and BMI loss in accordance with current recommendations 17 , and health-related quality of life (HRQoL). HRQoL was estimated with the physical and mental components summary score using RAND-36/ ® (SF-36/RAND ® ) scale (RAND Corp, USA) 18 , as well as the disease-specific obesity problems (OP) scale 19 . Short-term complications were also compared across procedures (RYGB and SG) and stratified by ACS without heart failure, and heart failure alone.

Statistics
Continuous variables assuming a normal distribution are presented as the mean(s.d.) or as the median with interquartile range (i.q.r.) when not assuming a normal distribution. Categorical variables are presented as numbers (n) and proportions (per cent). Differences in proportions were evaluated with conditional logistic regression or the Fisher's exact test. Associations of heart disease with binary outcomes were assessed using a conditional logistic regression model, with continuous outcome variables using a linear mixed-effects model, and with HRQoL outcomes using a linear quantile mixed-effects model with fixed variables and random intercepts for each matched group. After matching, the balance between cases and controls was evaluated by calculating the standardized difference, measuring difference in units of the pooled s.d. Based on this balance evaluation, all the analyses were conditional to matching and adjusted for smoking. Interaction between heart disease and smoking, if present, was also tested in the mixed-effects models. The OR, mean difference (MeD), and median difference (MdD) are presented as measures of association. Due to multiple calculations of secondary endpoints, the Bonferroni-Holm method was used to adjust for multiple comparisons 20 . Missing data were handled by listwise deletion. SPSS ® version 25 (IBM, Armonk, New York, USA) and Stata version 17.0 (StataCorp, College Station, Texas, USA) were used for statistical analyses.

Ethics
The study was approved by the Swedish Ethical Review Authority (ref. no. 2020-03005) and conducted in accordance with the standards of the 1964 Helsinki Declaration and its later amendments.

Results
During the study interval, 56 999 patients were identified in the Scandinavian Obesity Surgery Registry. A total of 1165 patients met the criteria with primary SG/RYGB and previous history of ACS, or heart failure. The matching procedure resulted in two groups without any relevant differences in patient characteristics ( Table 1).
Information on the operation and intraoperative complications were available for all patients. Follow-up for postoperative complications at day 30 was available for 1131 patients in the heart disease group (97.1 per cent), and 5687 in the control group (97.6 per cent). The follow-up rate for weight loss was 88.0 per cent (n = 984 of 1118) in the heart disease group and 89.2 per cent (n = 5022 of 5630) in the control group at one year, and 64.9 per cent (n = 657 of 1013) in the heart disease group and 69.2 per cent (n = 3581 of 5176) in the control group at two years after surgery. HRQoL is reported with some delay and only at some of the included surgical centres (44 centres reported HRQoL data, but not all centres reported all years). Therefore, information on   HRQoL was available at baseline for 788 patients in the heart disease group at baseline and 3970 patients in the control group.

Short-term safety outcomes
Mean operating time was 72.0(35.8) min in the heart disease group versus 70.2(33.5) min in the control group (P = 0.185). No difference in the risk for intraoperative complications was seen (n = 33 (2.8 per cent) in the heart disease group versus n = 186 (3.2 per cent) in the control group; OR 0.89, 95 per cent c.i. 0.61 to 1.30, P = 0.543). Median duration of hospital stay was 1 (i.q.r. 1-2) day in the heart disease group versus 1 (i.q.r. 1-2) day in the control group (P = 0.993).
No difference in the risk for overall complications, nor serious postoperative complications was seen. A higher risk for cardiovascular complications during the first 30 days was seen in the heart disease group compared with the control group (1.1 per cent versus 0.2 per cent, P , 0.001). Death within 90 days of surgery was also more common in the group with previous heart disease (n = 8; 0.7 per cent), compared with n = 2 (0.03 per cent), in the control group (P , 0.001). All patients who died in the group with previous heart disease underwent a RYGB, whereas both patients in the control group underwent an SG. The cause of death for patients with heart disease was a cardiovascular event for five patients, septicaemia in two, and unknown for one patient. The causes of death for the controls were an acute cerebrovascular event for one patient and pulmonary embolism for one patient. No other significant differences were seen between the two groups in short-term postoperative safety outcomes ( Table 2).
When stratified by surgical approach, no difference was seen in overall occurrence of postoperative complications (9.0 per cent in the heart disease group compared with 8. An increased risk for any postoperative complication (11.2 per cent versus 5.5 per cent, OR 2.11, 95 per cent c.i. 1.21 to 3.67, P = 0.008) as well as serious postoperative complication (5.1 per cent versus 2.2 per cent, OR 2.30, 95 per cent c.i. 1.01 to 5.21, P = 0.046) was seen after SG in patients with heart disease compared with the control group. No statistically significant difference was noted for any of the specified complications for SG (Tables S1 and S2).
A lower risk for an intraoperative complication (1.8 per cent versus 3.6 per cent, OR 0.45, 95 per cent c.i. 0.25 to 0.92, P = 0.028) and a higher weight loss (as measured by EBMIL) both after the 1-and 2-year follow-up was seen in patients with ACS without heart failure compared with controls (Table S3). Patients with heart failure alone had an increased risk for a cardiovascular complication (1.2 per cent versus 0.2 per cent, OR 7.90, 95 per cent c.i. 2.20 to 28.37, P = 0.024) and a higher BMI loss after the 1-year follow-up compared with controls (Table S4). Similar patterns in complications were seen when data were stratified according to BMI (Tables S5 and S6).

Mid-term safety outcomes
No difference in overall complication rate from day 30 until 2 years after surgery was seen between the groups; however, with regard to specific complications, bowel obstruction or strictures occurred more often in the heart disease group ( Table 3).

Weight outcome
Mean(s.d.) BMI loss at 1 year after surgery for all patients in the study was 12.0(3.99) kg/m 2 , mean EBMIL 73.7(22.63) per cent and TWL 28.4(7.87) per cent with no differences between the heart Numbers are n (%) unless otherwise indicated. *Conditional logistic regression, adjusted for smoking, and interaction between heart disease and smoking. †Conditional logistic regression, adjusted for smoking; interaction term was not statistically significant and excluded in the model. ‡The mesenteric defect beneath the jejunojejunostomy was closed for 87 per cent in the heart disease group and 86 per cent in the control group. Petersen's space was closed during 84 per cent of the operations in both groups. disease group and the control group ( Table 2). Mean(s.d.) BMI loss at 2 years was 12.0(4.54) kg/m 2 , mean(s.d.) EBMIL was 74.0(24.41) per cent and TWL was 28.4(9.02) per cent with no differences between the heart disease group and the control group ( Table 2).

HRQoL
Patients with heart disease reported a lower physical quality of life before surgery compared with the control group. All aspects of HRQoL, as estimated with the summary scores from SF-36 and OP, improved for both groups, and no difference was seen between the groups either at 1 or 2 years after surgery ( Table 4).

Discussion
This study demonstrates that metabolic surgery can be performed safely in patients with previous heart disease (acute cardiovascular event, heart failure, or cardiomyopathy). The overall risk for early (less than 30 days) and late (30 days or more) complications was similar for patients with cardiovascular disease and the matched group that did not have cardiovascular disease; however, there was an increased risk for early cardiovascular complications, a higher 90-day mortality rate, and an increased risk for bowel obstruction or strictures in patients with previous heart disease. There was an increased risk for any early complications after SG compared with the control group; however, cardiovascular complications were only increased after RYGB in patients with previous heart disease. There was no difference in HRQoL after metabolic surgery in patients with or without previous heart disease. There was no difference in weight loss at 1 or 2 years of follow-up. Although the number of patients is low, in equivalence with a recent study from North America 11 , there was a 4.5-fold relative risk for cardiovascular complications in the group with previous heart disease; however, this needs to be put into the context of a significant reduction in both MACE and mortality seen after metabolic surgery in patients with previous cardiovascular disease 7,8 . The overall 90-day mortality seen in this study (0.1 per cent) is comparable to that reported in the literature (0.03-0.2 per cent) 21 . For those without previous heart disease the 90-day mortality rate was very low and for those with previous heart disease was slightly higher than rates reported in the literature. This elevated risk was driven by cardiovascular death. Although patients with previous heart disease had an increased risk for early postoperative mortality, the overall risk for mortality remains lower up to 8 years after surgery when compared with patients with heart disease who did not undergo metabolic surgery 7 .
Bowel obstruction or strictures were higher in the group with previous heart disease. The reason for this is not clear. There was no difference in mesenteric defects closure between the two groups. It is possible that patients in the group with previous heart disease were more likely to use medication that may increase the risk for ulcers and strictures. Also, patients with heart failure are more prone to have portal congestion and intestinal oedema 22 . The two groups were well matched with regard to preoperative co-morbidity other than heart disease, which makes it unlikely that differences in postoperative co-morbidity might influence the risk for late complications. Due to a small number of events, we could not stratify mid-term complications according to surgical procedure. However, a meta-analysis of published RCTs comparing late complications after RYGB and SG found no significant difference between the procedures 23 .
Current data regarding the role of metabolic surgery in the secondary prevention of cardiovascular disease are based on observational studies. Thus, patient recommendations need to be given with caution and no firm guidelines exist. Despite the strengths of the large nationwide study population and the use of high-quality data from several sources, this study has several limitations. First, this is an observational study, residual confounding factors may exist, and causality cannot be shown. As with all registry studies, coding errors may exist. On the other hand, this study was based on large nationwide registers with known high validity and degree of completeness. Second, the outcomes may differ depending on surgical method, BMI, sex, and severity of disease. When stratifying the results, on surgical method, type of heart disease, BMI, or sex, no major differences that would have an impact on the conclusions were seen; however, no differentiation of the severity of T2D was included in the study. While this was not an aim of the present study, the outcomes of metabolic surgery for patients with severe heart disease and T2D of different severity should preferably be the focus of future studies.
Although a careful preoperative cardiovascular work-up is needed, patients with severe obesity and heart disease should not be excluded from undergoing metabolic surgery considering the recently demonstrated positive effects of metabolic surgery in secondary cardiovascular prevention.